Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), also known as cluster of differentiation 66a (CD66a), is a member of the carcinoembryonic antigen (CEA) gene family and belongs to the immunoglobulin (Ig) superfamily CEACAM1 is upregulated in T and NK cells upon activation and its homophilic interactions lead to inhibition of lymphocytes cytotoxic effect. Studies of several human tumor types have suggested that the exploitation of the CEACAM1 pathway may permit immune evasion by tumors. Preclinical animal models of tumors have shown that blockade of CEACAM1 interactions by monoclonal antibodies (mAbs) can enhance the immune response to tumors. An estimated 1,660,290 new cases of cancer and 580,350 cancer-related deaths were seen in the United States in 2013.
Checkpoint Immunotherapy blockade has shown to be an exciting new venue of cancer treatment. Immune checkpoint pathways consist of a range of co-stimulatory and inhibitory molecules which work in concert in order to maintain self-tolerance and protect tissues from damage by the immune system under physiological conditions. Tumors take advantage of certain checkpoint pathways in order to evade the immune system. Therefore, the inhibition of such pathways has emerged as a promising anti-cancer treatment strategy (Pardoll, D. M., 2012, Nat Rev Cancer, 12, 252-264). Anti-tumor immunotherapy via CEACAM1 blockade is not limited in principle to any single tumor type, but may have activity in augmenting therapeutic immune response to a number of histologically distinct tumors.
The anti-cytotoxic T lymphocyte 4 (CTLA-4) antibody ipilimumab (approved in 2011) was the first immunotherapeutic agent that showed a benefit for the treatment of cancer patients (Robert et al., 2011, N. Engl. J. Med., Vol. 364, pages 2517-2526). The antibody interferes with inhibitory signals during antigen presentation to T cells. Anti-programmed cell death 1 (PD-1) antibody pembrolizumab (approved in 2014) blocks negative immune regulatory signaling of the PD-1 receptor expressed by T cells (Hamid, 2013, N. Engl. J. Med., Vol. 2, pages 134-144). Blocking antibodies of the PD-1/PL-L1 axis have shown promising results in several clinical trials in patients with various tumor types (Dolan and Gupta 2014, Cancer Control, Vol. 21, pages 231-237). An additional anti-PD-1 agent has been filed for regulatory approval in 2014 for the treatment of non-small cell lung cancer (NSCLC). Active research is currently exploring many other immune checkpoints, among them: lymphocyte activation gene 3 (LAG3), CD137, OX40 (also referred to as CD134), and killer cell immunoglobulin-like receptors (KIR) (Gelao et al., 2014, Toxins, Vol. 6, pages 914-933).
Humanized antibodies are antibodies from non-human species (e.g. murine antibodies) whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of “humanization” is usually applied to monoclonal antibodies developed for administration to humans, and performed when the process of developing a specific antibody involves generation in a non-human immune system (such as in mice). The protein sequences of antibodies produced in this way are distinct from antibodies occurring naturally in humans, and are therefore immunogenic when administered to human patients. Humanized antibodies are considered distinct from chimeric antibodies, which have protein sequences similar to human antibodies, but carry large stretches of non-human protein.
It is possible to produce a humanized antibody without creating a chimeric intermediate. Direct creation of a humanized antibody can be accomplished by inserting the appropriate CDR coding segments (responsible for the desired binding properties) into a human antibody scaffold, a process known as “CDR grafting”. In general, after an antibody is developed to have the desired properties in a mouse (or another non-human animal), the DNA coding for that antibody's CDRs can be sequenced. Once the precise sequences of the desired CDRs are known, these sequences are inserted into a construct containing the DNA for a human antibody framework.
WO 2010/125571 to the present inventors discloses a murine monoclonal antibody (MRG-1) produced by a specific hybridoma cell. The mAb is highly selective to CEACAM1 and does not cross-react with other members of the CEACAM family. WO 2013/054331 to the present inventors discloses a chimeric antibody (CM-10), also highly selective to CEACAM1.
Although there is progress in the field of immunotherapy, there remains a constant need for new treatments that are more effective and longer lasting and which involve novel targets and can work either as signal agents or in combination with known therapies in order to eventually generate long durable responses in cancer patients. There is an unmet need to provide humanized antibodies recognizing specific CEACAM proteins which are safer and more potent and can be used diagnostically and therapeutically in diseases involving CEACAM-proteins expression or activation.